This document discusses HIV-associated nephropathy (HIVAN). It begins by introducing HIVAN and its characteristic biopsy findings. It then covers the epidemiology, noting that HIVAN was previously the 3rd leading cause of end-stage renal disease in African Americans aged 20-64. The pathogenesis involves direct infection of renal epithelial cells by HIV. Treatment includes highly active antiretroviral therapy (HAART), ACE inhibitors, and steroids. Prognosis is generally poor without treatment but improved survival is seen with HAART, ACE inhibitors, and steroids. The kidney may serve as a viral reservoir even when levels are undetectable in blood.

1. Dr. M. A. Sood
Mombasa Dialysis Centre

2. INTRODUCTION
 Association btw HIV and renal disease was first
reported in 1984 in New York City and Miami.
 Reported series of HIV-sero+ve patient who developed
a renal syndrome characterized by progressive renal
failure and proteinuria.
 Most common biopsy finding was Focal segmental
Glomerulosclerosis(FSGS).

3.  HIV –associated nephropathy (HIVAN), formerly
known as AIDs-associated nephropathy , is
characterised by the following findings
 1. Nephrotic range proteinuria
 2. Azotemia
 3. Normal to large kidney on ultrasonographic images
 4. Normal pressure
 5. Focal segmental glomerulosclerosis(FSGS) on
biopsy findings

4. Epidemiology
 Incidence of end-stage renal disease(ESRD) due to
HIVAN has increased more rapidly than any other
etiology of renal disease.
 In 1999, HIVAN became the 3rd leading cause of ESRD
in Africa Americans aged 20-64
 Since introduction of HAART, the incidence of ESRD
due to HIVAN has decreased.

5. Kidney Disease is on the Rise in HIV Patients in the
United States
Selik, JAIDS. 2002 Apr 1;29(4):378-87.
Trends in diseases reported on U.S. death
certificates that mentioned HIV infection

6. 2001 USRDS annual report

7. Racial Predilection of HIVAN
 The marked racial predilection of HIVAN for blacks
and Hispanic patients has been reported previously.
 The marked racial disparity in HIVAN suggests genetic
factors are important determinant of HIVAN
pathogenesis( Hailemariam et al)
 Nearly 25% of patients with HIVAN have 1st degree or
2nd degree family member with ESRD, and black
patient with HIVAN are 5.4times more likely to have a
1st degree or 2nd degree relative with ESRD than are
black patients without renal disease.

8.  The Duffy antigen/receptor for chemokines(DARC)
has been proposed as a candidate gene involved in
HIVAN pathogenesis.
 The DARC promoter has a high prevalence of
polymorphisms in black patients
 Liu et al have demonstrated increased DARC expression
in renal specimens from children with HIVAN and
haemolytic uremic syndrome.

9. Pathogenesis OF HIVAN
 Role of HIV infection of Renal Epithelial Cells
Until recently, it was unknown whether HIV infection of
renal parenchymal cell caused HIVAN directly or
Whether HIVAN was an indirect renal response to
HIV-induced immune dysregulation.
Studies using an HIV transgenic mouse model of HIVAN
have provided important insight into HIVAN
pathogenesis.

10.  HIV-transgene is expressed in renal glomerular and
tubular epithelial cells that transgene expression in
renal epithelial cells was required for development of
the HIVAN phenotype.
 Further support for a role of direct infection of renal
parenchymal cells in HIVAN was provided by a
macque model of HIV-induced renal disease( stephen
et al)

11. In situ hybridization for HIV-mRNA in HIVAN.

12.  The mechanism by which HIV gain entry into renal
epithelial cells is UNKNOWN. CD4, receptor for HIV and
CCR5 and CXCR4, the major co-receptors for HIV are
not expressed in most renal epithelial cells.

13. The kidney as a Reservior for
HIV
 Infection of renal epithelial cells by HIV has important
implication for HIV seropositive patient not only
because it contributes to renal disease but also the
kidney may be an important reservoir for HIV.
 Bruggeman et al detected HIV detected HIV by both
RNA in situ hybridization and DNA in situ PCR in three
patients who had undetectable viral load in peripheral
blood samples.

14.  Winston et al reported despite an undetectable viral load
in the peripheral blood while on HAART, the patients
continued to express HIV in renal epithelial cells as
determined by RNA in situ hybridization.
 Thus , even in the face of an optimal virologic response
to antiretroviral therapy and clinical remission of
HIVAN.
 HIV infection persisted in the renal epithelium and
the virus remained transciptionally active at a low level

15. HISTOPATHOLOGICAL
ASPECTS

16. Patterns of glomerular and tubulo-interstitial disease in HIV positive patients
Glomerular disease N = 127 Tubulo-interstitial disease N = 9
Focal segmental
glomerulosclerosis
Membrano-proliferative GN
Minimal change disease
Membranous glomerulopathy
Lupus-like nephritis
Amyloidosis
Acute post-infectious GN
Focal segmental necrotising GN
Haemolytic uraemic syndrome
IgA nephropathy
Immunotactoid glomerulopathy
End-stage kidney
88
13
6
5
4
4
2
1
1
1
1
1
Interstitial nephritis
Drug induced
Idiopathic
Acute tubular necrosis
Malignant lymphoma
5
2
3
3
1
D’Agati & Appel 1998

17. Normal renal biopsy (PAS stain)

18. Pseudo-crescent formation with collapsing glomerulopathy in
a patient with HIV

19. Dilated tubules with micro-cyst formation in a patient with HIV

20. Florid interstitial nephritis in a patient with HIV

21. Mesangial proliferation and focal sclerosis

22.  One of the pathologic hallmark of HIVAN is focal
Glomerulosclerosis, often of the collapsing type.
 The collapsing lesions are associated with vigorous
podocyte proliferation and loss of podocyte
differentiationmarkers, including
synaptopodin, podocalyxin.

23. HIVAN: Investigations
 Nephrotic range proteinuria is usually present
 Serum complement levels normal
 CD4 counts variable, from normal to low
 Presence of HIV antibodies
Normal kidney, less echogenic than liver Normal sized, but extremely echogenic
kidney in pt with HIVAN
• Renal ultrasound - usually shows echogenic kidneys with preserved
or enlarged size of more than 12 cm in spite of severe renal
insufficiency

24. Treatment
 The following discussion will focus on the best
available evidence concerning the efficacy of:-
 1. HAART
 2.ACE-inhibitors
 3. Steroids in treatment of HIVAN

25. HIVAN: Possible mechanisms of benefit of HAART
 Suppression of viral replication felt to be a key factor
 ?viral proteins/cytokines released during active viral replication
directly cytopathic to kidneys
– Recent evidence (Foster, 2004) suggests ‘non-viral’ actions of HAART
may be equally important
– Protease inhibitors shown to inhibit reactive O2 species (ROS)
generation and ROS-linked apoptosis of murine mesangial cells
independent of HIV gene expression
– This anti-apoptotic non-virologic effect of protease inhibitors may be
important in humans

26. HAART and HIVAN Incidence
12-Year Cohort Study
No AIDS AIDS
Cases
per
1000
person-
years
0
5
10
15
20
25
30
35
40
45
Lucas GM, et al. AIDS. 2004;20:18(3):541-546.
Numbers in bars represent point estimates for HIV-associated
nephropathy incidence in cases per 1000 person-years. Brackets
above bars represent upper limits of 95% confidence intervals.
No Antiretroviral
Therapy
Nucleoside Reverse
Transcriptase
Inhibitor Therapy
Highly Active
Antiretroviral
Therapy
Presumed HIV-Associated Nephropathy
Incidence Stratified by AIDS Status and
Antiretroviral Use
2.6
5.0
26.3
14.4
6.8
0.0
 Risk of HIVAN low in
patients without AIDS
 NO HIVAN when HAART
used without AIDS
occurrence
 Lower HIVAN associated
with NRTI and HAART
use compared with no
ART in patients with AIDS
(p < 0.001 for trend)

27. ACE-inhibitors
 The effect of ACE inhibitors on HIVAN progression
has also been studied.
 Kimmel et al reported an increase in renal survival
associated with captopril usage in a retrospective case-
control study of 18 patients with biopsy proven HIVAN
 Burns et al offered 10mg/d fosiniopril after 12-24wk,
renal function remained stable.

28. Steriods
 Prednisone has been found in several studies to be
associated with reduced risk of progressive renal
failure with HIVAN
 The only study in the HAART era evaluating the
efficacy of prednisone in patients with HIVAN was
recently published by Szczech et al.
 After multivariate analysis of several clinical variable ,
the association between prednisone and reduced rate
of decline in Creatinine clearance remained highly
significant

29. Differential Diagnosis of ARF in HIV
 HIV Related
 HIVAN
 Thrombotic Microangiopathy
 Membranoproliferative GN
 Immune Complex GN (MPGN or Lupus Like)
 Medication
 Indinavir, Tenofovir, Sulfadiazine, Pentamidine,
Sulfamethoxazole and trimethoprim
 Other
 Usual causes in general population – pre-renal, etc
 AIN – multiple medication exposures
 Hepatitis B and C related disease
 Rhabdomyolysis – statins and PI’s

30. Prognosis
 The data regarding prognosis for renal and patient
survival after diagnosis of HIVAN are biased by the
fact the majority of patients are referred to
nephrologist late in the course of their renal disease
and HIV infection.
 Patients with HIVAN who are not treated with
HAART, ACE-inhibitors, or prednisone, generally have
a poor prognosis with a mean time to progression to
ESRD of 1 to 3 months.

31.  Clinical variables associated with progression of renal
failure including:
 1. Elevated serum Creatinine
 2. Low CD4 count
 3. High HIV viral load
 4. Higher Level of proteinuria
 5. Previous antiretroviral therapy

32. Conclusion
 HIVAN was 1st described 26years ago, its important
cause of renal failure among black patients.
 Since introduction of HAART, the incidence ESRD has
decreased.
 Although data are lacking, the prevalence of HIVAN is
probably highest in Africa, where it will likely emerge
as a major cause of morbidity and mortality as the
prognosis of AIDS survival improves.
 HIV infection of renal epithelial cells components of
HIVAN pathogenesis.

33.  Renal epithelial cells are a newly identified viral
reservoir and a separate replicating compartments
distinct from blood.
 Viral genes are necessary for causing renal disease.

34. Questions?